Digital Commons Network^™

The Effects Of Covid-19 Mrna Vaccine On Adolescence Gynecological Well-Being, Shih-Chiao Tseng, Dana Cherry, Mansoo Ko, Steven R Fisher, Michael Furtado, Shuo-Hsiu Chang

Faculty, Staff and Student Publications

PURPOSE: Evidence suggests that transcranial direct current stimulation (tDCS) can enhance motor performance and learning of hand tasks in persons with chronic stroke (PCS). However, the effects of tDCS on the locomotor tasks in PCS are unclear. This pilot study aimed to: (1) determine aggregate effects of anodal tDCS combined with step training on improvements of the neural and biomechanical attributes of stepping initiation in a small cohort of persons with chronic stroke (PCS) over a 4-week training program; and (2) assess the feasibility and efficacy of this novel approach for improving voluntary stepping initiation in PCS.

METHODS: A total …

Immunogenicity Phase Ii Study Evaluating Booster Capacity Of Nonadjuvanted Aks-452 Sars-Cov-2 Rbd Fc Vaccine, David G Alleva, Eline A Feitsma, Yester F Janssen, Hendrikus H Boersma, Thomas M Lancaster, Thillainaygam Sathiyaseelan, Sylaja Murikipudi, Andrea R Delpero, Melanie M Scully, Ramya Ragupathy, Sravya Kotha, Jeffrey R Haworth, Nishit J Shah, Vidhya Rao, Shashikant Nagre, Shannon E Ronca, Freedom M Green, Stephen A Shaw, Ari Aminetzah, Schelto Kruijff, Maarten Brom, Gooitzen M Van Dam, Todd C Zion

Faculty, Staff and Students Publications

AKS-452, a subunit vaccine comprising an Fc fusion of the ancestral wild-type (WT) SARS-CoV-2 virus spike protein receptor binding domain (SP/RBD), was evaluated without adjuvant in a single cohort, non-randomized, open-labelled phase II study (NCT05124483) at a single site in The Netherlands for safety and immunogenicity. A single 90 µg subcutaneous booster dose of AKS-452 was administered to 71 adults previously primed with a registered mRNA- or adenovirus-based vaccine and evaluated for 273 days. All AEs were mild and no SAEs were attributable to AKS-452. While all subjects showed pre-existing SP/RBD binding and ACE2-inhibitory IgG titers, 60-68% responded to AKS-452 …

Revascularization Strategies For Acute And Chronic Mesenteric Ischemia: A Narrative Review, Jacob J Gries, Takashi Sakamoto, Bing Chen, Hafeez Ul Hassan Virk, Mahboob Alam, Chayakrit Krittanawong

Faculty, Staff and Students Publications

Mesenteric ischemia is a challenging condition characterized by insufficient blood perfusion to the mesentery and, consequently, intestinal tissues that continues to perplex clinicians. Despite its low prevalence, the condition’s variable clinical presentation and elusive radiographic diagnosis can delay life-saving interventions in the acute setting and deteriorate the quality of life of patients when left undiagnosed or misdiagnosed. Purpose: Review and summarize recent diagnostic updates and emergent intervention strategies for acute and chronic mesenteric ischemia. Methods: A narrative review of all relevant studies from January 2022 through September 2023. Results: A total of 11 studies from MEDLINE, supplemented with 44 studies …

Predictive Modeling And Cryo-Em: A Synergistic Approach To Modeling Macromolecular Structure, Michael R Corum, Harikanth Venkannagari, Corey F Hryc, Matthew L Baker

Faculty, Staff and Student Publications

Over the last 15 years, structural biology has seen unprecedented development and improvement in two areas: electron cryo-microscopy (cryo-EM) and predictive modeling. Once relegated to low resolutions, single-particle cryo-EM is now capable of achieving near-atomic resolutions of a wide variety of macromolecular complexes. Ushered in by AlphaFold, machine learning has powered the current generation of predictive modeling tools, which can accurately and reliably predict models for proteins and some complexes directly from the sequence alone. Although they offer new opportunities individually, there is an inherent synergy between these techniques, allowing for the construction of large, complex macromolecular models. Here, we …

The Pathogenicity Of Vancomycin-Resistant Enterococcus Faecalis To Colon Cancer Cells, Li Zhang, Mingxia Deng, Jing Liu, Jiajie Zhang, Fangyu Wang, Wei Yu

Faculty, Staff and Student Publications

BACKGROUND: The aim of this study was to investigate the pathogenicity of vancomycin-resistant Enterococcus faecalis (VREs) to human colon cells in vitro.

METHODS: Three E. faecalis isolates (2 VREs and E. faecalis ATCC 29212) were cocultured with NCM460, HT-29 and HCT116 cells. Changes in cell morphology and bacterial adhesion were assessed at different time points. Interleukin-8 (IL-8) and vascular endothelial growth factor A (VEGFA) expression were measured via RT-qPCR and enzyme-linked immunosorbent assay (ELISA), respectively. Cell migration and human umbilical vein endothelial cells (HUVECs) tube formation assays were used for angiogenesis studies. The activity of PI3K/AKT/mTOR signaling pathway was measured …

Novel Ancestry-Specific Primary Open-Angle Glaucoma Loci And Shared Biology With Vascular Mechanisms And Cell Proliferation, Valeria Lo Faro, Arjun Bhattacharya, Wei Zhou, Dan Zhou, Ying Wang, Kristi Läll, Masahiro Kanai, Esteban Lopera-Maya, Peter Straub, Priyanka Pawar, Ran Tao, Xue Zhong, Shinichi Namba, Global Biobank Meta-Analysis Initiative, Serena Sanna, Ilja M Nolte, Yukinori Okada, Nathan Ingold, Stuart Macgregor, Harold Snieder, Ida Surakka, Jonathan Shortt, Chris Gignoux, Nicholas Rafaels, Kristy Crooks, Anurag Verma, Shefali S Verma, Lindsay Guare, Daniel J Rader, Cristen Willer, Alicia R Martin, Milam A Brantley, Eric R Gamazon, Nomdo M Jansonius, Karen Joos, Nancy J Cox, Jibril Hirbo

Faculty, Staff and Student Publications

Primary open-angle glaucoma (POAG), a leading cause of irreversible blindness globally, shows disparity in prevalence and manifestations across ancestries. We perform meta-analysis across 15 biobanks (of the Global Biobank Meta-analysis Initiative) (n = 1,487,441: cases = 26,848) and merge with previous multi-ancestry studies, with the combined dataset representing the largest and most diverse POAG study to date (n = 1,478,037: cases = 46,325) and identify 17 novel significant loci, 5 of which were ancestry specific. Gene-enrichment and transcriptome-wide association analyses implicate vascular and cancer genes, a fifth of which are primary ciliary related. We perform an extensive statistical analysis of …

Susceptible Windows Of Prenatal And Postnatal Fine Particulate Matter Exposures And Attention-Deficit Hyperactivity Disorder Symptoms In Early Childhood, Wei-Jen Chen, Alison M Rector-Houze, Mònica Guxens, Carmen Iñiguez, Michael D Swartz, Elaine Symanski, Jesús Ibarluzea, Antonia Valentin, Aitana Lertxundi, Llúcia González-Safont, Jordi Sunyer, Kristina W Whitworth

Faculty, Staff and Student Publications

Few prior studies have explored windows of susceptibility to fine particulate matter (PM_2.5) in both the prenatal and postnatal periods and children’s attention-deficit/hyperactivity disorder (ADHD) symptoms.

We analyzed data from 1,416 mother-child pairs from the Spanish INMA (INfancia y Medio Ambiente) Study (2003–2008). Around 5 years of age, teachers reported the number of ADHD symptoms (i.e., inattention, hyperactivity/impulsivity) using the ADHD Diagnostic and Statistical Manual of Mental Disorders. Around 7 years of age, parents completed the Conner’s Parent Rating Scales, from which we evaluated the ADHD index, cognitive problems/inattention, hyperactivity, and oppositional subscales, reported as age- and sex-standardized …

Recombinant Rod Domain Of Vimentin Reduces Sars-Cov-2 Viral Replication By Blocking Spike Protein-Ace2 Interactions, Fong Wilson Lam, Cameron August Brown, Shannon Elizabeth Ronca

Faculty, Staff and Students Publications

Although the SARS-CoV-2 vaccination is the primary preventive intervention, there are still few antiviral therapies available, with current drugs decreasing viral replication once the virus is intracellular. Adding novel drugs to target additional points in the viral life cycle is paramount in preventing future pandemics. The purpose of this study was to create and test a novel protein to decrease SARS-CoV-2 replication. We created the recombinant rod domain of vimentin (rhRod) in E. coli and used biolayer interferometry to measure its affinity to the SARS-CoV-2 S1S2 spike protein and the ability to block the SARS-CoV-2–ACE2 interaction. We performed plaque assays …

Multivalent Cytomegalovirus Glycoprotein B Nucleoside Modified Mrna Vaccines Did Not Demonstrate A Greater Antibody Breadth, Hsuan-Yuan Wang, Leike Li, Cody S Nelson, Richard Barfield, Sarah Valencia, Cliburn Chan, Hiromi Muramatsu, Paulo J C Lin, Norbert Pardi, Zhiqiang An, Drew Weissman, Sallie R Permar

Faculty, Staff and Student Publications

Human cytomegalovirus (HCMV) remains the most common congenital infection and infectious complication in immunocompromised patients. The most successful HCMV vaccine to date, an HCMV glycoprotein B (gB) subunit vaccine adjuvanted with MF59, achieved 50% efficacy against primary HCMV infection. A previous study demonstrated that gB/MF59 vaccinees were less frequently infected with HCMV gB genotype strains most similar to the vaccine strain than strains encoding genetically distinct gB genotypes, suggesting strain-specific immunity accounted for the limited efficacy. To determine whether vaccination with multiple HCMV gB genotypes could increase the breadth of anti-HCMV gB humoral and cellular responses, we immunized 18 female …

Late Cardiotoxicity From The Tyrosine Kinase Inhibitor, Dasatinib: Pleural Effusions, Pulmonary Arterial Hypertension, And Right Heart Failure, Mark Jay Zucker, Andrew M. Zucker

The VAD Journal

Despite the remarkable progress made over the past few decades in the management of patients with both solid and hematologic malignancies, radiation- and chemotherapy-related cardiotoxicity remains an ongoing problem. This is true even for newer highly targeted therapies, including tyrosine kinase inhibitors (TKIs). This report presents a case of late/severe right heart dysfunction secondary to pulmonary hypertension, developed after ten years of therapy with dasatinib. We also review the history of this known, but often unrecognized, and potentially reversible complication, and we suggest treatment options. Additionally, this case highlights the remarkable effectiveness of TKIs in patients with chronic myelogenous leukemia …

P90rsk Pathway Inhibition Synergizes With Cisplatin In Tmem16a Overexpressing Head And Neck Cancer, Abdulkader Yassin-Kassab, Suman Chatterjee, Nayel Khan, Nathaniel Wang, Vlad C Sandulache, Eric H-B Huang, Timothy F Burns, Umamaheswar Duvvuri

Faculty, Staff and Students Publications

Head and neck squamous cell carcinoma (HNSCC) constitutes one of the most common types of human cancers and often metastasizes to lymph nodes. Platinum-based chemotherapeutic drugs are commonly used for treatment of a wide range of cancers, including HNSCC. Its mode of action relies on its ability to impede DNA repair mechanisms, inducing apoptosis in cancer cells. However, due to acquired resistance and toxic side-effects, researchers have been focusing on developing novel combinational therapeutic strategies to overcome cisplatin resistance. In the current study, we identified p90RSK, an ERK1/2 downstream target, as a key mediator and a targetable signaling node against …

Retreatment Strategies For Cases Containing Calcium Silicate-Based Root Canal Sealers: A Comprehensive Review, Hussain Al Akam, Hyeon-Cheol Kim, Ji Wook Jeong

Faculty, Staff and Student Publications

This review explores the field of retreatment strategies for cases filled with calcium silicate-based root canal sealers. Since the introduction of calcium silicate-based materials in dentistry, calcium silicate-based root canal sealers have become popular among dentists because of their biocompatibility, bioactivity, and sealing ability. Therefore, effective retreatment strategies are indispensable. This article aims to identify the challenges associated with the removal of calcium silicate-based sealers themselves and removal of gutta-percha with the sealers during retreatment, evaluate current techniques and materials, and provide future directions for research in this field. Regarding the strategies of removal of root canal sealers, calcium silicate-based …

Uterine Leiomyomata As A Cause Of Abdominal Compartment Syndrome In The Postpartum Period, Mason Hui, Baha Sibai, Alvaro Montealegre, Mateo G Leon

Faculty, Staff and Student Publications

Uterine leiomyomas are common benign smooth muscle tumors that often occur during the reproductive years. Although many cases may not result in significant complications, negative pregnancy outcomes have been associated with the size and location of the fibroids. Degeneration of fibroids can occur as early as the late first trimester when they undergo significant volumetric growth, contributing to pain during pregnancy. While myomectomy is typically avoided during pregnancy, conservative management with anti-inflammatory medications may be effective. Surgical removal or preterm delivery may be necessary if symptoms persist. Abdominal compartment syndrome (ACS) is a rare condition characterized by sustained elevated intra-abdominal …

Immunity From Nk Cell Subsets Is Important For Vaccine-Mediated Protection In Hpv+ Cancers, Madison P O'Hara, Ananta V Yanamandra, K Jagannadha Sastry

Faculty, Staff and Student Publications

High-risk human papillomaviruses (HPVs) are associated with genital and oral cancers, and the incidence of HPV+ head and neck squamous cell cancers is fast increasing in the USA and worldwide. Survival rates for patients with locally advanced disease are poor after standard-of-care chemoradiation treatment. Identifying the antitumor host immune mediators important for treatment response and designing strategies to promote them are essential. We reported earlier that in a syngeneic immunocompetent preclinical HPV tumor mouse model, intranasal immunization with an HPV peptide therapeutic vaccine containing the combination of aGalCer and CpG-ODN adjuvants (TVAC) promoted clearance of HPV vaginal tumors via induction …

Deciphering Early-Stage Molecular Mechanisms Of Negative Pressure Wound Therapy In A Murine Model, Yu-Chiau Shyu, Ting-Shuo Huang, Hua-Sheng Chiu, Pavel Sumazin, Xin-Yu Lin, Po-Cheng Liao, Cai-Cin Liou, Fang-Chia Hsu, Jyuan-Siou Lin, Chih-Chin Hsu, Pang-Hung Hsu, Chi-Chin Sun, Chien-Tzung Chen

Faculty, Staff and Students Publications

Negative Pressure Wound Therapy (NPWT) is a commonly employed clinical strategy for wound healing, yet its early-stage mechanisms remain poorly understood. To address this knowledge gap and overcome the limitations of human trials, we establish an NPWT C57BL/6JNarl mouse model to investigate the molecular mechanisms involved in NPWT. In this study, we investigate the intricate molecular mechanisms through which NPWT expedites wound healing. Our focus is on NPWT's modulation of inflammatory immune responses and the concurrent orchestration of multiple signal transduction pathways, resulting in shortened coagulation time and reduced inflammation. Notably, we observe a significant rise in dickkopf-related protein 1 …

Long Trimer-Immunization Interval And Appropriate Adjuvant Reduce Immune Responses To The Soluble Hiv-1-Envelope Trimer Base, Hongying Duan, Angela R Corrigan, Cheng Cheng, Andrea Biju, Christopher A Gonelli, Adam S Olia, I-Ting Teng, Kai Xu, Sijy O'Dell, Sandeep Narpala, Mike Castro, Leonid Serebryannyy, Jennifer Wang, Danealle K Parchment, Edward K Sarfo, Jelle Van Schooten, John-Paul Todd, Shuishu Wang, Darcy R Harris, Hui Geng, Alexander J Jafari, Vrc Production Program, Ruth A Woodward, Nicole A Doria-Rose, Kathryn E Foulds, Adrian B Mcdermott, Marit J Van Gils, Richard A Koup, Theodore C Pierson, Peter D Kwong, John R Mascola

Faculty, Staff and Student Publications

Soluble 'SOSIP'-stabilized HIV-1 envelope glycoprotein (Env) trimers elicit dominant antibody responses targeting their glycan-free base regions, potentially diminishing neutralizing responses. Previously, using a nonhuman primate model, we demonstrated that priming with fusion peptide (FP)-carrier conjugate immunogens followed by boosting with Env trimers reduced the anti-base response. Further, we demonstrated that longer immunization intervals further reduced anti-base responses and increased neutralization breadth. Here, we demonstrate that long trimer-boosting intervals, but not long FP immunization intervals, reduce the anti-base response. Additionally, we identify that FP priming before trimer immunization enhances antibody avidity to the Env trimer. We also establish that adjuvants Matrix …

Cpsf3 Inhibition Blocks Pancreatic Cancer Cell Proliferation Through Disruption Of Core Histone Mrna Processing, Abdulrahman A Alahmari, Aditi H Chaubey, Venkata S Jonnakuti, Arwen A Tisdale, Carla D Schwarz, Abigail C Cornwell, Kathryn E Maraszek, Emily J Paterson, Minsuh Kim, Swati Venkat, Eduardo Cortes Gomez, Jianmin Wang, Katerina V Gurova, Hari Krishna Yalamanchili, Michael E Feigin

Duncan NRI Faculty and Staff Publications

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with limited effective treatment options, potentiating the importance of uncovering novel drug targets. Here, we target cleavage and polyadenylation specificity factor 3 (CPSF3), the 3′ endonuclease that catalyzes mRNA cleavage during polyadenylation and histone mRNA processing. We find that CPSF3 is highly expressed in PDAC and is associated with poor prognosis. CPSF3 knockdown blocks PDAC cell proliferation and colony formation in vitro and tumor growth in vivo. Chemical inhibition of CPSF3 by the small molecule JTE-607 also attenuates PDAC cell proliferation and colony formation, while it has no effect on cell proliferation …

A Small Molecule With Big Impact: Mrtx1133 Targets The Krasg12d Mutation In Pancreatic Cancer, Daoyan Wei, Liang Wang, Xiangsheng Zuo, Anirban Maitra, Robert S Bresalier

Faculty, Staff and Student Publications

KRAS mutations drive oncogenic alterations in numerous cancers, particularly in human pancreatic ductal adenocarcinoma (PDAC). About 93% of PDACs have KRAS mutations, with G12D (∼42% of cases) and G12V (∼32% of cases) being the most common. The recent approval of sotorasib (AMG510), a small-molecule, covalent, and selective KRASG12C inhibitor, for treating patients with non-small cell lung cancer represents a breakthrough in KRAS targeted therapy. However, there is a need to develop other much-needed KRAS-mutant inhibitors for PDAC therapy. Notably, Mirati Therapeutics recently developed MRTX1133, a small-molecule, noncovalent, and selective KRASG12D inhibitor through extensive structure-based drug design. MRTX1133 has demonstrated potent …

Sting Licensing Of Type I Dendritic Cells Potentiates Antitumor Immunity, Jian Wang, Suxin Li, Maggie Wang, Xu Wang, Shuqing Chen, Zhichen Sun, Xiubao Ren, Gang Huang, Baran D Sumer, Nan Yan, Yang-Xin Fu, Jinming Gao

Faculty, Staff and Student Publications

Stimulator of interferon genes (STING) is an immune adaptor protein that senses cyclic GMP-AMP (cGAMP) in response to self or microbial cytosolic DNA as a danger signal. STING is ubiquitously expressed in diverse cell populations including cancer cells with distinct cellular functions such as activation of type I interferons, autophagy induction, or triggering apoptosis. It is not well understood whether and which subsets of immune cells, stromal cells, or cancer cells are particularly important for STING-mediated antitumor immunity. Here using a polymeric STING-activating nanoparticle (PolySTING) with a “shock-and-lock” dual activation mechanism, we show type 1 conventional dendritic cell (cDC1) is …

Mutant P53 Protects Triple-Negative Breast Adenocarcinomas From Ferroptosis In Vivo, Denada Dibra, Shunbin Xiong, Sydney M Moyer, Adel K El-Naggar, Yuan Qi, Xiaoping Su, Elisabeth K Kong, Anil Korkut, Guillermina Lozano

Faculty, Staff and Student Publications

The TP53 tumor suppressor gene is mutated early in most of the patients with triple-negative breast cancer (TNBC). The most frequent TP53 alterations are missense mutations that contribute to tumor aggressiveness. Here, we used an autochthonous somatic TNBC mouse model, in which mutant p53 can be toggled on and off genetically while leaving the tumor microenvironment intact and wild-type for p53 to identify physiological dependencies on mutant p53. In TNBCs that develop in this model, deletion of two different hotspot p53R172H and p53R245W mutants triggers ferroptosis in vivo, a cell death mechanism involving iron-dependent lipid peroxidation. Mutant p53 protects cells …

Inter-Individual Variations In Circadian Misalignment-Induced Nafld Pathophysiology In Mice, Nobuya Koike, Yasuhiro Umemura, Hitoshi Inokawa, Isao Tokuda, Yoshiki Tsuchiya, Yuh Sasawaki, Atsushi Umemura, Naoko Masuzawa, Kazuya Yabumoto, Takashi Seya, Akira Sugimoto, Seung-Hee Yoo, Zheng Chen, Kazuhiro Yagita

Faculty, Staff and Student Publications

Pathological consequences of circadian misalignment, such as shift work, show considerable individual differences, but the lack of mechanistic understanding hinders precision prevention to prevent and mitigate disease symptoms. Here, we employed an integrative approach involving physiological, transcriptional, and histological phenotypes to examine inter-individual differences in pre-symptomatic pathological progression, preceding irreversible disease onset, in wild-type mice exposed to chronic jet-lag (CJL). We observed that CJL markedly increased the prevalence of hepatic steatosis with pronounced inter-individual differences. Stratification of individual mice based on CJL-induced hepatic transcriptomic signature, validated by histopathological analysis, pinpoints dysregulation of lipid metabolism. Moreover, the period and power of …

Cpsf3 Inhibition Blocks Pancreatic Cancer Cell Proliferation Through Disruption Of Core Histone Mrna Processing, Abdulrahman A Alahmari, Aditi H Chaubey, Venkata S Jonnakuti, Arwen A Tisdale, Carla D Schwarz, Abigail C Cornwell, Kathryn E Maraszek, Emily J Paterson, Minsuh Kim, Swati Venkat, Eduardo Cortes Gomez, Jianmin Wang, Katerina V Gurova, Hari Krishna Yalamanchili, Michael E Feigin

Faculty, Staff and Students Publications

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with limited effective treatment options, potentiating the importance of uncovering novel drug targets. Here, we target cleavage and polyadenylation specificity factor 3 (CPSF3), the 3′ endonuclease that catalyzes mRNA cleavage during polyadenylation and histone mRNA processing. We find that CPSF3 is highly expressed in PDAC and is associated with poor prognosis. CPSF3 knockdown blocks PDAC cell proliferation and colony formation in vitro and tumor growth in vivo. Chemical inhibition of CPSF3 by the small molecule JTE-607 also attenuates PDAC cell proliferation and colony formation, while it has no effect on cell proliferation …

Cyp2a6 Activity And Cigarette Consumption Interact In Smoking-Related Lung Cancer Susceptibility, Mulong Du, Junyi Xin, Rui Zheng, Qianyu Yuan, Zhihui Wang, Hongliang Liu, Hanting Liu, Guoshuai Cai, Demetrius Albanes, Stephen Lam, Adonina Tardon, Chu Chen, Stig E Bojesen, Maria Teresa Landi, Mattias Johansson, Angela Risch, Heike Bickeböller, H-Erich Wichmann, Gad Rennert, Susanne Arnold, Paul Brennan, John K Field, Sanjay S Shete, Loïc Le Marchand, Geoffrey Liu, Angeline S Andrew, Lambertus A Kiemeney, Shan Zienolddiny, Kjell Grankvist, Mikael Johansson, Neil E Caporaso, Angela Cox, Yun-Chul Hong, Jian-Min Yuan, Matthew B Schabath, Melinda C Aldrich, Meilin Wang, Hongbing Shen, Feng Chen, Zhengdong Zhang, Rayjean J Hung, Christopher I Amos, Qingyi Wei, Philip Lazarus, David C Christiani

Faculty, Staff and Student Publications

Cigarette smoke, containing both nicotine and carcinogens, causes lung cancer. However, not all smokers develop lung cancer, highlighting the importance of the interaction between host susceptibility and environmental exposure in tumorigenesis. Here, we aimed to delineate the interaction between metabolizing ability of tobacco carcinogens and smoking intensity in mediating genetic susceptibility to smoking-related lung tumorigenesis. Single-variant and gene-based associations of 43 tobacco carcinogen-metabolizing genes with lung cancer were analyzed using summary statistics and individual-level genetic data, followed by causal inference of Mendelian randomization, mediation analysis, and structural equation modeling. Cigarette smoke-exposed cell models were used to detect gene expression patterns …

A Mutation In F-Actin Polymerization Factor Suppresses The Distal Arthrogryposis Type 5 Piezo2 Pathogenic Variant In Caenorhabditis Elegans, Xiaofei Bai, Harold E Smith, Luis O Romero, Briar Bell, Valeria Vásquez, Andy Golden

Faculty, Staff and Student Publications

The mechanosensitive PIEZO channel family has been linked to over 26 disorders and diseases. Although progress has been made in understanding these channels at the structural and functional levels, the underlying mechanisms of PIEZO-associated diseases remain elusive. In this study, we engineered four PIEZO-based disease models using CRISPR/Cas9 gene editing. We performed an unbiased chemical mutagen-based genetic suppressor screen to identify putative suppressors of a conserved gain-of-function variant pezo-1[R2405P] that in human PIEZO2 causes distal arthrogryposis type 5 (DA5; p. R2718P). Electrophysiological analyses indicate that pezo-1(R2405P) is a gain-of-function allele. Using genomic mapping and whole-genome sequencing approaches, we identified a …

Pulmonary Fibrosis Stakeholder Summit: A Joint Nhlbi, Three Lakes Foundation, And Pulmonary Fibrosis Foundation Workshop Report, Sydney B Montesi, Christian R Gomez, Michael Beers, Robert Brown, Ishanu Chattopadhyay, Kevin R Flaherty, Christine Kim Garcia, Brigitte Gomperts, Lida P Hariri, Cory M Hogaboam, R Gisli Jenkins, Naftali Kaminski, Grace Hyun J Kim, Melanie Königshoff, Martin Kolb, Darrell N Kotton, Jonathan A Kropski, Joseph Lasky, Chelsea M Magin, Toby M Maher, Mark Mccormick, Bethany B Moore, Cheryl Nickerson-Nutter, Justin Oldham, Anna J Podolanczuk, Ganesh Raghu, Ivan Rosas, Steven M Rowe, William T Schmidt, David Schwartz, Jessica E Shore, Cathie Spino, J Matthew Craig, Fernando J Martinez

Faculty, Staff and Students Publications

Despite progress in elucidation of disease mechanisms, identification of risk factors, biomarker discovery, and the approval of two medications to slow lung function decline in idiopathic pulmonary fibrosis and one medication to slow lung function decline in progressive pulmonary fibrosis, pulmonary fibrosis remains a disease with a high morbidity and mortality. In recognition of the need to catalyze ongoing advances and collaboration in the field of pulmonary fibrosis, the NHLBI, the Three Lakes Foundation, and the Pulmonary Fibrosis Foundation hosted the Pulmonary Fibrosis Stakeholder Summit on November 8–9, 2022. This workshop was held virtually and was organized into three topic …

Frequency Specific Optogenetic Stimulation Of The Locus Coeruleus Induces Task-Relevant Plasticity In The Motor Cortex, Ching-Tzu Tseng, Hailey F Welch, Ashley L Gi, Erica Mina Kang, Tanushree Mamidi, Sahiti Pydimarri, Kritika Ramesh, Alfredo Sandoval, Jonathan E Ploski, Catherine A Thorn

Faculty, Staff and Student Publications

The locus ceruleus (LC) is the primary source of neocortical noradrenaline, which is known to be involved in diverse brain functions including sensory perception, attention, and learning. Previous studies have shown that LC stimulation paired with sensory experience can induce task-dependent plasticity in the sensory neocortex and in the hippocampus. However, it remains unknown whether LC activation similarly impacts neural representations in the agranular motor cortical regions that are responsible for movement planning and production. In this study, we test whether optogenetic stimulation of the LC paired with motor performance is sufficient to induce task-relevant plasticity in the somatotopic cortical …

Multifaceted Roles For Stat3 In Gammaherpesvirus Latency Revealed Through In Vivo B Cell Knockout Models, Chad H Hogan, Shana M Owens, Glennys V Reynoso, Yifei Liao, Thomas J Meyer, Monika A Zelazowska, Bin Liu, Xiaofan Li, Anna K Grosskopf, Camille Khairallah, Varvara Kirillov, Nancy C Reich, Brian S Sheridan, Kevin M Mcbride, Benjamin E Gewurz, Heather D Hickman, J Craig Forrest, Laurie T Krug

Faculty, Staff and Student Publications

Cancers associated with the oncogenic gammaherpesviruses, Epstein-Barr virus and Kaposi sarcoma herpesvirus, are notable for their constitutive activation of the transcription factor signal transducer and activator of transcription 3 (STAT3). To better understand the role of STAT3 during gammaherpesvirus latency and the B cell response to infection, we used the model pathogen murine gammaherpesvirus 68 (MHV68). Genetic deletion of STAT3 in B cells of CD19cre/+Stat3f/f mice reduced peak MHV68 latency approximately sevenfold. However, infected CD19cre/+Stat3f/f mice exhibited disordered germinal centers and heightened virus-specific CD8 T cell responses compared to wild-type (WT) littermates. To circumvent the systemic immune alterations observed in …

Sugar-Binding And Split Domain Combinations In Repeats-In-Toxin Adhesins From Vibrio Cholerae And Aeromonas Veronii Mediate Cell-Surface Recognition And Hemolytic Activities, Mustafa Sherik, Robert Eves, Shuaiqi Guo, Cameron J Lloyd, Karl E Klose, Peter L Davies

Faculty, Staff and Student Publications

Many pathogenic Gram-negative bacteria use repeats-in-toxin adhesins for colonization and biofilm formation. In the cholera agent Vibrio cholerae, flagellar-regulated hemagglutinin A (FrhA) enables these functions. Using bioinformatic analysis, a sugar-binding domain was identified in FrhA adjacent to a domain of unknown function. AlphaFold2 indicated the boundaries of both domains to be slightly shorter than previously predicted and assisted in the recognition of the unknown domain as a split immunoglobulin-like fold that can assist in projecting the sugar-binding domain toward its target. The AlphaFold2-predicted structure is in excellent agreement with the molecular envelope obtained from small-angle X-ray scattering analysis of …

The Il6/Jak/Stat3 Signaling Axis Is A Therapeutic Vulnerability In Smarcb1-Deficient Bladder Cancer, Chandra Sekhar Amara, Karthik Reddy Kami Reddy, Yang Yuntao, Yuen San Chan, Danthasinghe Waduge Badrajee Piyarathna, Lacey Elizabeth Dobrolecki, David J H Shih, Zhongcheng Shi, Jun Xu, Shixia Huang, Matthew J Ellis, Andrea B Apolo, Leomar Y Ballester, Jianjun Gao, Donna E Hansel, Yair Lotan, H Courtney Hodges, Seth P Lerner, Chad J Creighton, Arun Sreekumar, W Jim Zheng, Pavlos Msaouel, Shyam M Kavuri, Nagireddy Putluri

Faculty, Staff and Student Publications

SMARCB1 loss has long been observed in many solid tumors. However, there is a need to elucidate targetable pathways driving growth and metastasis in SMARCB1-deficient tumors. Here, we demonstrate that SMARCB1 deficiency, defined as genomic SMARCB1 copy number loss associated with reduced mRNA, drives disease progression in patients with bladder cancer by engaging STAT3. SMARCB1 loss increases the chromatin accessibility of the STAT3 locus in vitro. Orthotopically implanted SMARCB1 knockout (KO) cell lines exhibit increased tumor growth and metastasis. SMARCB1-deficient tumors show an increased IL6/JAK/STAT3 signaling axis in in vivo models and patients. Furthermore, a pSTAT3 selective inhibitor, TTI-101, reduces …

Protecting Human And Animal Health: The Road From Animal Models To New Approach Methods, Barbara L F Kaplan, Alan M Hoberman, William Slikker, Mary Alice Smith, Emanuela Corsini, Thomas B Knudsen, M Sue Marty, Sonya K Sobrian, Suzanne C Fitzpatrick, Marcia H Ratner, Donna L Mendrick

Faculty, Staff and Student Publications

Animals and animal models have been invaluable for our current understanding of human and animal biology, including physiology, pharmacology, biochemistry, and disease pathology. However, there are increasing concerns with continued use of animals in basic biomedical, pharmacological, and regulatory research to provide safety assessments for drugs and chemicals. There are concerns that animals do not provide sufficient information on toxicity and/or efficacy to protect the target population, so scientists are utilizing the principles of replacement, reduction, and refinement (the 3Rs) and increasing the development and application of new approach methods (NAMs). NAMs are any technology, methodology, approach, or assay used …